Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
  • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
  • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
  • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
  • C07D501/36—Methylene radicals, substituted by sulfur atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/02—Preparation
  • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
  • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
  • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
  • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
  • C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
  • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
  • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
  • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
  • C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
  • C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings

Definitions

• R is an a-amino-adipoyl group.
• compounds according to the invention containing a CH S group attached to the 3-position of the cephalosporin nucleus are of especial value as intermediates in the process of application Serial No. 381,580, filed July 9, 1964, for the production of compounds having potent antibacterial activity.
• R is a carboxylic acyl group or a hydrogen atom
• Y is the group SO SSO or SCX-, X
• R is an aliphatic, aryl, araliphatic, heterocyclic, or heterocyclic substituted aliphatic group or, where Y is the group SO or SCO, a hydroxyl group, or alkoxyl group respectively and Z is a cation.
• the compounds according to the invention may be prepared by reaction in a strongly polar medium of a compound of the general formula J 0211 (III) in which R has the meaning defined above, with a compound of the general formula R YH (IV) or a soluble salt thereof where R and Y have the meanings defined above, the resulting compound where R is a hydrogen atom being thereafter, if desired acylated.
• R may represent an acyl group in general terms one may use specific acyl derivatives representative of alkanoyl, alkenoyl, substituted alkanoyl e.g. aralkanoyl, aryloxyalkanoyl, S-arylthioalkanoyl and S-aralkylthioalkanoyl etc.
• acyl derivatives include those having the general formulae:
• R'(CH ),,CO where R is aryl, cycloalkyl, substituted aryl, substituted cycloalkyl or heterocyclic and n is an integer from 14.
• R is aryl, cycloalkyl, substituted aryl, substituted cycloalkyl or heterocyclic and n is an integer from 14. Examples of this group include phenylacetyl, nitrophenylacetyl, phenylpropionyl, cyclopentylactyl, thienyl-Z-acetyl, thienyl-3-acetyl and cyclohexylacetyl.
• alkyl group may be straight or branched and, if desired, may be interrupted by an oxygen or a sulphur atom or substituted by one or more halogen atoms. Examples of such groups include hexanoyl, heptanoyl, octanoyl and butylthioacetyl.
• alkenyl group may be straight or branched and, if desired, may be interrupted by an oxygen or a sulphur atom. Examples of such groups include acrylyl, crotonyl and allylthioacetyl.
• R'OCR"R"'.CO where R has the meaning defined under (i) or is an alkyl group and R" and R' are the same or are different and each is a hydrogen atom or an alkyl, aryl or heterocyclic group.
• R has the meaning defined under (i) or is an alkyl group and R" and R' are the same or are different and each is a hydrogen atom or an alkyl, aryl or heterocyclic group.
• An example of such a group is phenoxyacetyl.
• RSCRR"'.CO-- where R, R" and R' are as defined above.
• thio groups include S- phenylthioacetyl, S-chlorophenylthioacetyl and S-bromophenylthioacetyl.
• examples of such a group include S-benzylthioacetyl, benzylthiopropionyl and [3- phenethylthioacetyl.
• RCO- where R has the meaning defined above.
• examples of such groups include benzoyl, substituted benzoyl and cyclopentanoyl. Where the benzoyl group is substituted the substituents may be alkyl or alkoxy and the substituents may be in the 2- or 2- and 6-positions.
• An example of a 2,6-disubstituted benzoyl group is, therefore, 2,6-dimethoxybenzoyl.
• R should be selected from acyl groups of section (i).
• R may be a-aminoadipoyl i.e. the acyl group of cephalosporin C.
• the reaction may conveniently be effected by heating the reactants in solution in the strongly polar medium; that is, maintaining the reactants in solution at an elevated temperature, such as, for example, 70 C. or even 100 C., preferably 37100 C., for periods ranging from a few days to a few minutes until the desired derivative is obtained in optimum yield.
• the reaction proceeds particularly well when carried out at a temperature of about 37 C. for a period of from 48 to 120 hours.
• the reactants are advantageously employed in a ratio of about 1 molar equivalent of the compound of general Formula III to 1-10 molar equivalents of nucleophile (iv).
• the pH value of the reaction solution is advantageously maintained within the limits 3.5-8, preferably 4.5-7.
• the pH of the solution should be adjusted to the desired value by the addition of a bufiering agent such as sodium acetate or, when employing an alkali metal salt of the cephalosporin of the general Formula III, by the addition of, for example, acetic acid.
• a bufiering agent such as sodium acetate or, when employing an alkali metal salt of the cephalosporin of the general Formula III, by the addition of, for example, acetic acid.
• the reaction appears to proceed by a polar or ionic mechanism it is necessary to employ a strongly polar medium for the reaction to proceed at a measurable rate.
• the most generally suitable solvent is water but in those cases in which the nucleophile is not very soluble in water a mixture of water and a water-miscible organic solvent such as dimethylformamide, acetone or ethanol may be employed.
• the course of the reaction may be followed by observing physical characteristics such as ultraviolet and infrared spectra and optical rotation of aliquots withdrawn from the reaction mixture.
• physical characteristics such as ultraviolet and infrared spectra and optical rotation of aliquots withdrawn from the reaction mixture.
• PAC 7-phenylacetamidocephalosporanic acid
• thiobenzoic acid gives a derivative k-max. 240242 and 273-274 Ill 1, in which the development of the new maxima are associated with introduction of the thiobenzoate residue.
• the reaction product may be separated from the reaction mixture, which may contain, for example, unchanged starting material (III) and other substances, by a variety of processes including crystallisation, ionophoresis, paper chromatography by chromatography on ionexchange resins or counter-current distribution.
• the nucleophile may not only displace the acetate group of (ill) but may also displace the reactive group in R
• the group R is preferably an aryl or heterocyclic group, especially in the case of compounds where Y is the group -SCX.
• R is a phenyl group and X is an oxygen atom
• the compounds were obtained in high yield and in crystalline form.
• the resulting thiobenzoates possess antibiotic activity and also find particularly utility as intermediates in the preparation of other substances possessing antibiotic activity according to application No. 381,5 80.
• R may also be a substituted phenyl group e.g. substituted with cyano, nitro, lower alkoxy or lower alkylthio.
• the term lower indicates that the groups in question have 1-4 carbon atoms.
• the process according to the invention also leads to good yields of compounds of Formula II where the group Y-R has the formula S.CO. (R011 where the -S.CO. group is attached as, ,8 or 'y, preferably 0t or 'y and R is a C -C alkyl group or a fused benzene ring and n is 0, 1 or 2, e.g. using thiopicolinic acid or its sodium salt.
• S.CO. R011 where the -S.CO. group is attached as, ,8 or 'y, preferably 0t or 'y and R is a C -C alkyl group or a fused benzene ring and n is 0, 1 or 2, e.g. using thiopicolinic acid or its sodium salt.
• the compounds according to the invention having antibacterial activity may be formulated for administration in any convenient way by analogy with other antibiotic substances, such as penicillin and neomycin, and the invention thus includes within its scope a pharmaceutical composition comprising a compound of general Formula II, in which R is an acyl group, adapted for use in human or veterinary medicine.
• Such compositions may be presented for use in conventional manner with the aid of any necessary pharmaceutical carriers or excipients.
• the compounds may thus be made up into injecta'ble preparations either in solution or suspensionv in suitable media e.g. sterile, pyrogen-free Water or as dry preparations suitable for the extempore preparation of injectable preparations.
• suitable media e.g. sterile, pyrogen-free Water or as dry preparations suitable for the extempore preparation of injectable preparations.
• the compositions may further take the form of preparations for topical use e.g. lotions, ointments or creams, formulated with suitable excipients for such preparations.
• the compositions may also take the form of tablets or capsules or liquids for oral administration.
• the compounds may be formulated in a manner conventional in veterinary medicine particularly .for injection as veterinary cerates.
• the dosages employed in human medicine on adults will range from 200 mg. per dose upwards, administered for example four times a day.
• Solutions and suspensions of the antibacterial sub stances according to the invention may also contain further solubilising substances, particularly physiologically acceptable water-miscible organic solvents for the active material.
• antibacterial compounds according to the invention may be administered in combination with other antibacterial antibiotics especially the penicillins such as penicillin G and/or 'tetracyclines.
• Example fi flfg j t f, 'thienylacemmi' acid with sodium-7-(2-thienylacetamido)-cephalosporan- 0)'cep ate This is shown in Example 12(b).
• the solution was heated at 50 for 29 hr. under nitrogen.
• the mixture 1 hour and then filtered.
• the damp solid was dissolved 7 in a mixture of acetone (240 ml.) and water '(80 ml.) at 40, and concentrated hydrochloric acid (8.5 m
• D Grade reaction mixture acidified and purified as free Optical rotations are for dioxan (c, 1%), except for the sodium salt 5, which was determined in EtOHI-I2O (2:1), the sodium salt 12 and the acids 7, 13, 15a and 15b determined in dimethylsulphoxidc, and the potassium salt 15, determined in acetone-water (1 :1)
• Ultraviolet absorptions are for solutions in 0.1 M- phosphate buffer ad usted to pH 6.0 except for compound 12(Na), which was determined in water and for compounds 7 and 10 which were determined in ethanol.
• Example 15.-3-benz0ylthi0methyl-7-(2'-thienylacetamido)-ceph-3-em-4-0ic acid (a) Sodium 7-(2'-thienylacetamido)cephalosporanate (4.27 kg.), sodium thiobenzo-ate solution (40% w./v.; 5.35 1.), sodium dihydrogen orthop'hosphate dihydrate (1.88 kg.), orthop hosphoric acid (7.27 ml.), and water (27.8 litres) were heated together at 90 with stirring for 1 hr. The controlled pH of the reaction mixture was 4.5 at the start (rising to 5.2 at the finish of the reaction. The reaction mixture was cooled to 10 for 30 mins. and the crystalline sodium B-(benzoylthiomethyl) 7 (2 thienylacetarnido) ceph 3 em- 4-oate filtered off.
• the sodium salt was suspended in 50% aq. acetone (50 m1.) and covered with ethyl acetate (100 m1.) while 2N-hydrochloric acid was added. The mixture was shaken until nearly all the solid was dissolved. The acetone was removed in vacuo and the layers were separated. The aqueous layer was extracted with more ethyl acetate (50 rnl.), the extracts were combined, washed with water and dried (MgSO Evaporation gave a white solid (4.2 g.) which was crystallised cfrom boiling 2:1 acetone-water (180 ml.) to give the title compound (1.6 g., 25.8%), 138 (dioxan), Amax.
• Example 1 7.4-carb0xy-7-phenylacetamidoceph-S-em- 3-ylmethyl p-tolyl-sulphone Sodium 7-phenylacetamidocephalosporanate (5.0 g.) was dissolved in water (15 ml.) and sodium p-toluenesulphinate (10.8 g., 5 equiv.) was dissolved in a minimum of water (40 ml.). The solutions were filtered through a sintered disk to remove dust and, after mixing, were in cubated at 47 for 26 hours (total volume 55-60 ml., including washings).
• the resulting cream powder (4.85 g.) was found, by paper chromatography, to be contaminated with sodium p-toluene sulphinate; this was removed by slurrying twice with ice water (1 x 20 ml., 1 X 10 ml.) and filtering rapidly (the washings appeared to contain appreciable quantities of dissolved product).
• the product was finally freeze-dried to an off-white powder (3.3 g., 54%) Amax. 265 mp. (Ejfi 225) and 225 III/.1 (131 376) which was homogeneous on paper chromatography in the ethyl acetate and propanol-water systems, and on electrophoresis at pH 7.0.
• Mnax. 266 my (Ej' g 195) and 227 m i (El'fi' 324) (saturated solution in water at 20 C.), vmax. (Nujol) 1785 (,B-lactam), 1730 (COOH), 1660 and 1643 (CONH), 1137 (-SO 810 (para-substituted phenyl 'group).
• vmax. Nujol 1785 (,B-lactam)
• 1730 COOH
• 1660 and 1643 CONH
• 1137 -SO 810 (para-substituted phenyl 'group).
• Example 18 -'Reacti0n of 7-phenylacetamidocephalosporanic acid with thioacetic acid
• Example 19 Reaction of sodium 7-phenylacetamid0- cephalosporanate with sodium bisulphite Sodium 7-phenylacetamidocephalosporanate (53 mg.) and sodium metabisulphite (12.2 mg., 1 equiv.) were dissolved in water (2 ml.) and incubated at 47. The rotation of the reaction mixture was observed at intervals, but the changes in rotation were identical to those in aqueous solution of sodium 7-phenylacetamidocephalosporanate under similar conditions. After 30 hours, however, a product was evident on examination of the paper chromatograms under ultraviolet light.- In the ethyl acetate system it did not movefrom the origin (i.e.
• Example 20 -3-O-ethylxanthyl-7-(2'-thienylacetamido)- ceph-3-em-4-0ic acid 7-thienylacetamidocephalosporanic acid (3 g.) was dissolved in water (38 ml.) containing potassium hydrogen carbonate (0.66 g., 1 equiv.) and then potassium O-ethyl xanthate (1.8 g., 1.5 equiv.) was added. The mixture was filtered and incubated under nitrogen at 47 for 23 hours.
• the pH of the mixture was 6.5.
• Example 21 S-(7-D-5'-amin0-5'-carb0xypentanamid0-4- car-boxy-ceph-S-em-3-ylmethyl thiobenzoate Thiobenzoic acid (28.1 g., 0.203 mole) was dissolved in an aqueous solution of potassium hydroxide (11.4 g., 0.203 mole, in 220 ml. water) and the mixture was filtered and adjusted to pH 7.0 with dilute hydrochloric acid. Cephalosporin C dipotassium salt (50.0 g., 0.102 mole) was added and the mixture was stirred until solution was complete.
• the aqueous mother liquors (pH 7.3) of the crude product were adjusted to pH 2.0 under a layer of ethyl acetate with concentrated hydrochloric acid, and the aqueous phase was washed with ethyl acetate (1 x 150, 3 x ml.).
• the aqueous phase was adjusted to pH 2.4 with concentrated potassium hydroxide solution and the resulting precipitated oil was collected by decanting the mother liquors, triturated with water and then with acetone to give the crude cephalosporin C thiobenzoate (free acid) as a very light brown powder (16 g., 32.3%), [111 50 (c., 0.986, dioxan-wa'ter 1:1), Amax. (pH 6; 0.1 M- phosphate buffer) 2 11-242 111,. 131 3 .263, 6 13,000), 272 mp. (EVg 316,
• Example 22 --S-(7-amino-4-carboxyceph-3-em-3-ylmethyl) thiobenzoate
• Thiobenzoic acid (10.17 g., 0.074 mole) was dissolved in an aqueous solution of sodium hydroxide (2.95 g., 0.074 mole in 40 ml. water), the pH was adjusted to 7.0 with 2 N-hydrochloric acid, the mixture was filtered and treated with a solution of 7-amino-cephalosporanic acid (10.0 g., 0.037 mole) in aqueous sodium hydroxide (1.47 g., 0.037 mole in 40 ml. water) at pH 7.0.
• the reaction mixture was stirred and heated under nitrogen at 75-80" for 45 minutes. After being cooled and kept at for 3 hours a small amount of solid was removed by filtration and the filtrate was adjusted slowly to pH 3.6 (much of the product precipitated before this pH was reached).
• the product was collected, washed with water, triturated first with ether-acetone (50 ml., 30 ml.) then with acetone (30 ml.) and finally washed with more acetone (3 x 10 ml.) and dried in vacuo yielding the compound named in the title as a light brown powder (6.64 g., 51.5% Amax. (pH 6; phosphate buffer) 241-242 my (E12,, 352), 273-274 mu 12...
• Electrophoresis at pH 7.0 showed a major ultraviolet absorbent ninhydrin-positive (yellow) spot which moved as an acid at about half the speed of the 7-aminocephalosporanic acid standard.
• the major spot (ultraviolet absorption) remained on the origin though a faint ultraviolet absorbent spot (streaking) which moved as a base was observed.
• the ninhydrin colour reaction at this pH was very weak and indefinite.
• Example 23 S-(7-amino-4-carboxyceph-3-em-3- ylmethyl) thiopicolinate 7-aminocephalosporanic acid (2.0 g.) was suspended in water (25 ml.) and 2 N-sodium hydroxide solution was added until the solid dissolved and the solution'was at pH 7.0. A solution of sodium thiopicolinate (from 1.54 g. of thiopicolinic acid, 1.5 equiv.) in water (25 ml.) was added and the mixture was kept at 35 in an atmosphere of nitrogen for 4 days. The solution was cooled and filtered and the filtrate acidified to pH 5.0.
• sodium thiopicolinate from 1.54 g. of thiopicolinic acid, 1.5 equiv.
• the precipitated solid was the compound named in the title (0.66 g.; 26%); it was dried in vacuo, [oz] 74 (c. 1.00; 3%-NaHCO Amax. 2 9-231 m(u (EH5... 328; 6 11,500) 273-276 my vmax. 1800 cm.- (B-lactam), 1668 cm. (S-@O) and 1550 cm.- (CO R 0.56; electrophoresis at pH 1.9 showed movement as a cation (6.1 cms. at 15 volts per cm.). The compound gave a yellow colour with ninhydrin.
• Example 24 -S- 7-D-5 -amin0-5 -carb0xypen tanamido- 4 -carb0xyceph-3 -em-3 -ylmethyl thiopicoli ta'te
• the potassium salt of cephalosporin C 49:6 g. was dissolved in water (100 ml.) and the solution was adjusted to pH 7.0 with 6% potassium hydroxide solution.
• the activity of some of the compounds prepared according to the invention is shown in the following table.
• the Staph. aureus strains A and C were penicillin resistant while the ,strain B was penicillin sensitive.
• Tube dilution assay (y/ml.) Mouse rotection Dw/ sie/th s s cu aneous a min r tio Ex. N o. Gram-positive Gram-negative s a n Staph. aureus Staph. aureus Staph. aureus E. coli S. typhi- Pr. vulgart's Ps. pt/o- S. aureus E. colt strain A straln B strain 0 mtm'um cyanea strain B We claim: a 1. A compound of the formula:
• R is selected from the group consisting of (b) R (CH CO- where R is phenyl, nitrophenyl, chlorophenyl, bromophenyl, loweralkoxyphenyl, lower alkylphenyl, cycloalkyl or thienyl and n is an integer from 1 to 4 (c) R CO where R contains 2-7 carbon atoms and is alkyl, haloalkyl, carboxyalkyl, alkoxyalkyl or alkylthioalkyl (d) R CO where R contains 2-7 carbon atoms and is alkenyl, alkylthioalkenyl, alkenylthioalkyl, alkoxyalkenyl or alkenyloxyalkyl (e) R -O(CH -CO- where R and n are as defined above (f) R S(CH -CO where R and n are as defined above (g) R (CH S(CH (CH (CH)
• X is selected from the group consisting of sulphur and oxygen
• R is selected from the group consisting of lower alkyl
• R can also be 16 hydroxyl where Y is the group SO and loweralkoxyl where Y is the group SCO- and Zis selected from the group consisting of hydrogen, alkali metal, ammonium and quaternary ammonium.

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  • NL NL130098D patent/NL130098C/xx active
• 1963
  • 1963-07-15 GB GB27990/63A patent/GB1101424A/en not_active Expired
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• 1964
  • 1964-06-24 NO NO00153787A patent/NO128157B/no unknown
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  • 1964-07-08 FR FR981074A patent/FR1455030A/fr not_active Expired
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